Nu, nu-disubstituted-beta-halo-alkylamines



Fa'tented June 3, 1952 UNITED PATENT OFFIQE N, N-DISUBS-TITUTED=BETA-HALD ALKYLAMINES" James F. Kerwin and Glenn-1E, Ullyot, Philadel:

n a, nors to smit mineavrrenqnh Laboratories, Philadel of Pennsylvania N o Drawine This invention relates to certain-new chemical compounda'more particularly certain new halo gen-containing amines. and organicanemonganic salts thereof.

The new chemicalcompounds according to this invention have utility as physiologically active agents and, more'particularly; have adrenolytic or sympatholytic activity.

The new compounds accordingtouthis invention have the structure shown by the following formula:

in which: I

Y and Y are members of the group consisting of hydrogen, alkyl containing not more than 4 carbon atoms, benzyl, hydroxy, methoxy, ben

zyloxy, fluorine, chlorine andhbromine.

Wand W'are members of the group consisting of;hydrogen methyl; methoxy" andlchlori-ne.

R. i853- mer'nberz-of themgroup consisting of hydrogen andlmethyl. l

Xtisaa member oi. the. group consisting of chlorine. and' bromine.

Where hereinafter thev symbols Y, Y; W'}

R and Xware. mentioned; theyrwill indicate the substituents indicated for'rthemv in connection with: the above general formula;

The organicand inorganic salts contemplated by this inventionuincludes by way of example" salts-ofthe bases formedrwith organic: acids such,. for example, as glycolic; oxalic, malic;

camphorsulfonic, etc. and inorganicrac'ids-such as: for example;- sulfamic,-- hydrochloric; hydro bromic, sulfuric; phosphoric, etc.

such as are prepared with inorganic and organic acids having an ionization constant not less than 1 10- at 18 C. p v H The compounds in accordance with thisinvention and as identified by the above structural formula may be prepared variously by one of four general methods, from the following general description of whichprocedure for the preparation of all of the several-compounds will be apparent to those skilled in the art-1' More sp'ecifl;.- cally, the inorganic and organic salts wi ll' oe phia, Ra e Application September 2, 1950, Serial'No. 183,093

6 Claims; (Cl. 260-570.?)

l 2-; The compounds used as: starting: materialssfor: the synthesis of compounds of this invention are either known substances or, being made obvious, can be prepared by well known methods.

METHOD A A propylenehalohydrin or propylene oxide is addedto the sodium salt "eta-phenol of the type in refluxin -alcohol ta or y, the a coho henna he formula;

This samealoohol m y alsobe obtaine y;

reducing the:corresp nding'lietonewith"hydr gagi- In this process it is-advantageous to employ an excess or the primary amino alcohol.

The benzyl or'is'ubstituted benzyl group is introduced into the molecule by heating together he secon ar a n alc hol produced above ith a henz irhalme ra subs i" .halid This m be 1 un; utter .r presence of exc s. 199 91 or in he pres ence of aii acid bindinga nt such'a In most c se s t1 carrieu out Finally, the hydroxyl group of the alcohol amino is replaced by a halogen radical X, as in the METHOD B The secondary amino alcohol produced as in Method A above may also be obtained by means of the following reaction:

catalyst Q-o CHH JH- m This reduction may be carried out by dissolving equimolar quantities of ketone and amine in a solvent as, for example, methyl alcohol, ethyl alcohol, cyclohexane, etc. be agitated under hydrogen pressure in the presence of a suitable hydrogenation catalyst such as platinum, palladium or activated nickel.

The amino alcohol so produced may be treated as in Method A above to introduce the benzyl or substituted benzyl radical and the resulting product may then be treated as in the final step in Method A to obtain the halide.

METHOD C The ketones used as starting materials in Method B may also be used in the reaction which may be carried out in the same manner as described in Method B above.. The secondary amine resulting may then be reacted with ethylene or propylene halohydrin either in absence of a'solvent, or in the presence of a solvent such as ethyl alcohol, benzene, toluene or, xylene.v

Unless one employs an excess of the amine, it

will be advantageous to use an acid binding agent I The solution shouldsuch as potassium carbonate, sodium bicarbonate, or magnesium oxide:

@o-om-cn-om Y w /NH X-CHz-CH-QH Q-m-om-on-cm Y N-CH -CHOH w If desired, the tertiary amino alcohol may also be formed by heating the secondary amine together with an ethylene or propylene oxide; rather than utilizing the ethylene or propylene halohydrin in the reaction.

The product of this reaction may then be reacted with a thionyl halide as in Method A to replace the hydroxyl group with the halide radical.

METHOD D The secondary amine Q-o-cm-cn-cm Y NH W W! prepared in Method C above may also be made by an alternative method. This involves treating a primary amine of the type with a benzaldehyde or a substituted benzaldehyde and reducing the resulting mixture as described in Method B above. The tertiary amino alcohol is formed from the secondary amine by the use of either an alkylene halohydrin or an alkylene oxide as described in Method C, which amino alcohol is treated as in Method A to form the corresponding halide.

The following examples will be illustrative of the various types of compounds and of specific compounds in accordance with the invention and procedure for their preparation and will, it is believed, serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof, respectively, it being noted that the utility indicated for the several compounds flows from the,

elements of the general structure common to all of them.

Example '1 N-(phenoxyisopropyl) N -b enzyl-fi-chlorethylamine hydrochloride:

wise'=-wit eemarcccimg. Thestram .xcbn e ot th hydrogemc q 7, I H thefianother 55 g. of=thiony-l c'h-loride ds'gadtkida The' react" n miamre-isg-a icweewstand-waters tyfou'rho a'z-fewdropsof pyridine'are added and themi-xture heated =four= hours or rthe 's'tearit bath. The cooled reaction mixture iS-pbl-11ed into water, the crude productis washed with dilute sodium, bicarbonate solution and finally taken-up inbenz'en'e: The benzene distilled fiat. ordinary pressure" and" the residuedis'tille'd'dri vacuo to yield 60-70% of 1-phenoxy-'2=chloropr0- pane, B. P. 93-94 O./mm.

Step=,2.+-.-.'I o 4941s. of ethanolarnine; heated to approximately 150 C. in-a 500 ml. flask equipped with stirrer, condenser anddropping funnel, is added 465 g. of 1-phenoxy-2-ch1oropropane with mechanical stirring.- The reaction mixture is then hea-tedtd reflux ior three hours cooledand poured into -a liter of=waten The organic" layer 1s* extractedqinto ether and the ether solution} is extracted withdilute hydrochloric acid. Theaqueou'si-acid 's'olu'tion--is then made alkaline with 40% sodiumhydroxide solution and "the cre my base is extraeteddnto ether. Removal' ofthe-- ether leaves N- (plienoxyisoprop'yl) '-ethanolamine which; after -recrystallization--from--hexane,- melts at 70:5-72 C:

3:'"I-'o- 4-3- g. of r N- (phe'noxyisopropyl) ethanolam ine dissolved in 500 ml. of alcohol ina. r1000 ml; flash-equipped with stirrerand condensr is added 28 g. of benzyl chloride and 18.5; gr ot=sodium-bicarbonate.- The mixture is stirred w and--'refluxed for* ten-hoursand then appr'oxi-- mately-hal-f"the alcohol isremoved by distillat tion. The-remaining solutionis poured into 500 ml: of-iwater and the organic material extracted 4 with threelOOmI. portions of-ether, The-com bined ether extracts are washed with water-,dried over anhydrous potassium carbonate and filtered. After removal of the ether, the residue is distilled in vacuo to yield N (phenoxyisopropyl)=N- benzylethanolamine; B. P." 163=-16'8 -C'./0;2 mm. Step 4.-A solution of 20 g. of the-above amino alcohol is disso1ved in ml. of dry chloroform and. treated with; dry hydrogen chloride until acid. Then 'a solution .of 9 g". ofthionyl chloride in 50 ml. of dry chloroform is added and the reaction mixture is heated by a Water bath at 50 i'603-C..:for twohours. Most of the chloroform isremoyed by distillation under reduced pressure. Addition; of ether to, the =residuew-causes the product, ito. crystallize; After recrystallization. from. a. mixture. of; a-lcohol andethen the N-=(ph'enoxy'-.. isopropyl) a-N rbenzyl-flerchloroethylamine hydro-- chloridemeltsat-'137=5+140 C;

Their'ee base ofNephenbxyisopropiihNsbenzyl f1eolrlorethylamine:hydrochloride can be liberated k-the;followingzmanner. Thirty-four; grams .of tl eyhydrochloride :is.v suspended inz200. ml; of

water-icontaining-Am .g. of (sodium hydroxide and 6 etl-ii r l nen-crystallined fi phenoxy isopr gyg N benzyl-p-chlorethylamine meltsat-38=40 G? mamma a-methylph' pnronirhf Nmbeni ifl-chlorethylamine Hydrochloride:-

hatompound will. prepared: by Method; A: QYe-i assfollo-w.5*.-

pne ngoleso foecresol,amRZiOQmI-a oi -alcohol are."

hea xyp .-2.-.propano asl n-the mann e ess beda halagenation with-.thion l. hlarid r ofiqm -r ethyl eno h1or rawns? Be 9 9. Q-/ mhich.-.,irr. m.. is; reacted; with. ethanolamine; to f the sec-v nd-am m n lcohol. 1* orm thy1nl enoxx) prop lethanolam ne; M. 5:71-5:50? G- he yl o p swmtmduced Joyi-heatin the. S965 nder- Example. 1

ndar y mi qamoholi b n y chl ri e; h

resulting; te tiaryj Barlcohol: s, then. treate it h o xl-l hlo ide. 0; R1'0dl N* rm hXl-?-' enzy; efis hlo oethylamine 1 mmrle 3 N--= (m -'methylphenoxyisopropyl) -N -benzyl- .p#ohlorethy-laminmhydrochloride:-

ced-ure..-o Example -2: will. be followedusing. as. a starting material an. equimolar: amount of m-cresol in place 01:0-616501. The! m-cresol is converted with sodium hydroxide to the sodium salt ;;which"ist mefluxedrwith-propylenechlord: hydrin to obtain.m:methx phenoxyisopronan l;

Halogenation oi the m-methylphenoxyisopropanol with thionyl chloride, as in Example 1, forms m-methylphenoxyisopropyl chloride; B. P. 96.5-98 C. at 5 mm., which, in turn, is. reacted with ethanolamine-to form thesecondary amino the. mixture. is shaken-with v100 m1. of benzene. -.alcohol N-(m-methylphenoxyisopropyl) -'ethanol- After the soliddisappears. the.:benzene' layer is s separatemdried-nver anhydrous sodium sulfate,

filteredqandthesolvent :distilled at reduced pressure The. freebase whicl i remains solidifies amine, M. P. 57-58 C. The ben-zylgroup is introducedintoathe.molecule:byheatingthesecondary amino alcohol-.itogetlrer ewitl'rzbenzyl chloride;

The resulting. tertiary:aminmalocholsismconverted.a

propyl) N-benzyl5-chlorethylamine hydrochloride, M. P. 1333-134 C.

Example 4 N (p methylphenoxyisopropyl) .N benzylp-chlorethylamine hydrochloride: 1

1 (p methylphenoxy) 2 propanol boiling at I 101-106 C. /4 mm. 7

A stream of dry air is passed through 2'72 g. of cooled l-(p-methylphenoxy) 2-propanol while 143 g. of thionyl chloride is added dropwise. After three hours another 143 g. portion of thionyl chloride is added, followed by 3 ml. of dry pyridine. The reaction mixture is heated at YO-80 C. for 4 /2 hours, diluted with benzene, washed with sodium bicarbonate solution and distilled. The l-(p-methyl-phenoxy)2-chloropropane distills at 76-l'l C. at 2 mm.

The chloro'compound (225- g.) is introduced dropwise into 223 g. of refluxing ethanolamine. After three hours, the mixture is poured into water and the water-insoluble material is taken up in ether. The amine is extracted into dilute hydrochloric acid, the acid solution is made basic and extracted with ether. Distillation of the solvent leaves the solid N-(p-methylphenoxyisopropyl) ethanolamine, which melts at 68-70 C. after recrystallization from hexane.

A mixture of 100 g. of the above secondary amino alcohol, 60 g. of benzyl chloride, 25 g. of sodium carbonate and 500 ml. of alcohol is stirred and refluxed for nine hours. Half of the'alcohol is distilled off and the concentrated mixture is refluxed an additional three hours. The product is isolated by adding water, extracting the oil into ether and distilling. N-(p-methylphenoxyisopropyl)N-benzylethanolamine is collected at 159-163 C./0.22 mm.

Dry hydrogen chloride is passed into a solution of 69 g. of the tertiary amino alcohol and 200 ml. of chloroform. When the solution is acid, 30 g. of thionyl chloride is added and the solution refluxed for two hours. Removal of the solvent and recrystallization of the residue from alcohol and ether gives N-(p-methylphenoxyisopropyl)-N-benzylfl-chlorethylamine hydrochloride which melts at 138-140 C.

Example 5 N- (o chlorophenoxyisopropyl) N benzyl [3 chlorethylamine hydrochloride:

p-cresol as a starting material to' form l-(ochlorophenoxy) 2-propahol which distills at 109-,

114 C. at 3 mm. and forms a, p-nltrobenzoate ester which melts at 97-9'7.5 C.

Thev halogenation of the alcohol with thionyl chloride prepares the l-(o-chlorophenoxy) 2- chloropropane, B. P. 111-114 0'. per 5 mm., which is reacted with ethanolamine to form the secondary amino alcohol N- (o-chlorophenoxyisopropyl) ethanolamine. group is accomplished by heating the secondary amino alcohol with benzyl chloride. The resulting tertiary amino alcohol is treated with thionyl chloride to produce 'N-(o-chlorophenoxyisopropyl) N-benzyl-pchlorethylamine hydrochloride. M. P. 164-166" C.

Example 6 N (p chlorophenoxylsopropyl) N benzylfl-chlorethylamine hydrochloride:

mQ-oomon-om In this preparation the procedure of Example 4 will be followed using p-chlorophenol as a starting material. The p-chlorophenol is converted with sodium hydroxide to the sodium salt which is refluxed with propylene chlorohydrin to obtain the p-chlorophenoxyisopropanol, which distils at -130 C. at 6 mm. and forms a pnitrobenzoate ester, M. P. 76.5-77' C. r

The end product is prepared as described in Example 4 by halogenation of the p-chlorophenoxyisopropanol with thionyl chloride to form N-benzyl-fl-chlorethylamine hydrochloride, M.

P. 158.5-l59 C. 1

. Example 7 N (pmethoxyphenoxyisopropyl) N- benzyl-pchlorethylamine hydrochloride:

A solution of 372 g. of p-methoxyphenol, 500 ml. of alcohol, 120 g. of sodium hydroxide and ml. of water is heated to reflux while. 282 g. of

propylene chlorohydrin is added with stirring over a two hour period. The mixture is refluxed for three hours, cooled and filtered to remove sodium chloride. Most of the alcohol is distilled at reduced pressure and the residue is dissolved in 600 ml. of benzene. .The benzene solution is extracted with 10% sodium hydroxide solution, then with water and the solvent is evaporated.

The solid residue is p-methoxyphenoxyisopropanel, which melts at 63-64 C. after recrystallization from benzene-petroleum ether.

A slow stream of dry air is passed into a solution of 300 g. of pmethoxyphenoxyisopropanol and 1500 m1. of dry benzene while 146 g. of thionyl chloride is added dropwise with cooling,

The introduction of the N-benzyl siaeegcao After six hours anothrel ifiigp rtion of thionyl chloride is added and the solution allowed to astand overnight. Three icc.-"of-=dry-ppyridine is then added and *the "solution -frefluxe'd :for :six hours. The cooled benzene solution is poured into water and washed repeatedly with sodium bicarbonate solution. "Distillation of thesolvent followed :by distillation of the "'i'esidue'in vacuo yields p-methoxyphenoxyi6propyl chloride, B. P. 90-95 C./1 mm.

The 1- (p-methoxyphenoxy) -2-chloropropane is' reacted with ethano'lam'ine-to' formtlie second- -ary 'am'ino' alcohol- N-'(p -methoxyphenoxylsopifo- 1 p'yD' ethanolamine M;"P. 5 3-'55 C. The 'N-he'nzyl group is introduced 'by heating thescondary -fichlorethylamine hydrochloride:

anolamine. The introduction er the N- b rizyl ig'roiip is accomplished hyheating the secondary aminoalco'liol with ben'z'yl chloride. h The: resultingtrtiary' arriino alcohol; is treated with thionyl chloride to produce N (o-tert.-butylphenoxyisoride.

Eirample 9 N+-(pli'enoxyisopropy1') :N- (e-metuymerityn chlorethylaininehydrochloride:

N-(phenoxyisopropyl)-ethanolarnine, an intermediate in the synthesis of Example 1, is employe'das startingmaterial. The amino alcohol is reacted with o-methylhenzyl chloride in alcohol solution in the presence-of sodium bicarhonate in the same manner as described under Example v1 for benz-yl chloride. Thefinal :step,

reaction with thionyl chloride, is conducted 'in chloroform solution as described above to produce N {(phenox-yisopropyl) --N- (omethylben- 'zyD-B-bhlkarethylamine hydrochloride, M. P. 118 C.

? Eirizyl) 13 chlorthylamineihydrochloride:

. oomo11 ci13 "ma ma-01.1101

" CHE-o- N phenoxyisopropyl) *ethanolainine, *an mediate in the synthesis of Example 1, is employed as startin material. A solution of 39 g. of Netphenoxyisopropyl) ethanolamine;1-63, of p methoxybenzyl :chlori-de, and ml. of. dis-y benzene is refluxed for six hours One hundred ml. of water is added and the layers separated. After removal of the benzene, theres'id'iie is distilled to yield a smallam'o'unt 'cifstarting' amino alcohol and F22 g. of N-phenoxyisopropyl-N-(pmethoxybenzyl) -ethanolamirie, B.*P. 142157 C. at 0.2 mm.

Twenty-one grams of the'above tertiary amino alcohol is dissolved in 100 ml. of chloroform and "dry hydrogen "chloride is introduced until "-the solution is acid. :Tene'grarns'of thionyl' chlo tie -in -25 ml; of chloroform Fis added, "the solutfo -=is warmed to 0. for onemau :hour and when -'refiuxed"for"'an=hour. Remo'yeu or the "olvefit in vacuo leavesv'an oil 'Wh'ich solidifies n a'd'ditiOnof 'ether. The solid is"'collected*afid rerys- 'tallized from alcohol and ether, P. r4635- 14'T.5' C. v 1

"Exampiedz N (phenoxyi'sopropyl) N (3,4 dichlorobenzyl) 3-chlorethylamine" hydrochloride:

N-(phenoxy'isopropyl) -ethanolamine, an intermediate in the synthesis of Example 1, is emfpl'oyed l as stai'tin g'material. Thejlamino alcohol is "fea'cted wi th ;3,4-iii-ch1erz}be y1 "amen-(s1 solution in the pj sep 15f carp onat'e in'the -'sar ne inanner as d efscrihjed Example :1 for "benzyl "chloride. The-final 't p,

reaction with th'ionyl chIoriltle ;is conducted in chloroform 'fsolutionfas described "ab'oyfe fto cue-e -N=e p1j1enoxyisopropy1)j wuss -m"eltsfa --ch lorethylamine hydrochloride which t146 C. I

botdmple 12 N (phenoxyisopropyl) -N (3,4 dimethoxybenzyl) -@-chlorethylamine hydrochloride:

N- (phenoxyisopropyl) -N-eth a nolamine, an intermedi'ate -m the syn'ths'isof Example 1, is ""employedasstartingmaterial.

. -sljlution 'of "=48 g. of N-tphenexyisbprbiiyo etlianolamine, --'23 =g. or 3,4-'-dimetho'xybefizyl bie- '*mide"arid-150-ml. or toluene is heated gr from room temperature to 11 'o.;ovra of 1% hours and iheldfatjthat "taint ature an hour.

v ,Q' The "cooled reaction mixture is "ex- 1 1 tracted with water and'the organic layer distilled. After removal of the solvent, the residue is distilled'in vacuo, yielding N-phenoxyisopropyl N (3,4 dimethoxybenzyl) ethanolchloride, M. P. 128.5-1295" C.

r ,l Example 13 -N methylphenoxyisopropyl) N (omethylbenzyl) 3-chlorethylamine hydrochloride:

, 'N- (o-methylphenoxyisopropyl) ethanolamine, an intermediate in the synthesis of Example 2, is employed as a starting material. The amino alcohol is reacted with o-methylbenzyl chloride in alcohol solution in the presence of sodium .bicarbonate in the same manner as described .under Example 1 for 'benzyl chloride. The final step, reaction with thionyl chloride, is conducted in chloroform solution as described above to produce N-(phenoxyisopropyl) -N-(o-methylbcnzyl) fi-chlorethylamine hydrochloride.

Example 1 4 N (phenoxyisopropyl) N benzyl 1 amino- 2-chloropropane hydrochloride:

Q-oom-on-cm got. a

'7 in the preparation of this compound the 1 phenoxyisopropyl-2-chloropropane is reacted with isopropanolamine instead of ethanolamine 1 under the conditions described in Example 1.

The resulting secondary amino alcohol, M. P.

SQ-71 C. is treated with benzyl chloride to prepare the N-benzyl derivative, which distils at 149-151.5 C./0.2 mm. The resultin tertiary amino alcohol is converted to the halide by. treatment with thionyl chloride to produce 'N-(phenoxyisopropyl) N benzyl 1 amino 2 chlo ropane hydrochloride, M. P. 146-147 C.

Example 15 N-(phenoxyisopropyl) -N benzyl ,6 bromoethylamine hydrobromide:

N-(phenoxyisopropyl) -N-benzyl ,3 hydroxyethylamine is formed as an intermediate in the process in Example 1. In the final step the tertiary amino alcohol is reacted with hydrogen bromide and thionyl bromide in place of hydrogen chlorideand thionyl chloride to form N-(phexyis p pvll-N benzyl B bromoethylamine hydrobromide, M. P. 134.5136.5 C.

' N (p-tert.-butylphenoxyisopropyl) -N benzyl fi-chlorethylamine hydrochloride:

G or.

The procedure of Example 1 will be followed in the preparation of this compound, replacing the 1-phenoxy-2-propanol with an equimolar amount of 1-(p-tertiary butyl-phenoxy)-2-propanol as a starting material. The halide of this alcohol which is formed by reaction with thionyl chloride is reacted with ethanolamine to form the secondary amino alcohol N-(p-tertiary-butyl phenoxyisopropyl) N ethanolamine. The introduction of the N-benzyl group is accomplished as described in Example 1 in the presence of sodium bicarbonate. The resultin tertiary amino alcohol is converted to the halide by reaction with thionyl chloride to form N-(ptert.-butylphenoxyisopropyl)N-benzy1;3 chlorethylamine hydrochloride, M. P. 158.5-159 0.

Example 17 N-'(o-sec.-buty1phenoxyisopropyl) -N benzylfl-chlorethylamine hydrochloride:

The procedure of Example 1 will be followed in the preparation of this compound, replacing the l-phenoxy-Z-propanol with an equimolar amount of 1- (o-sec.-butyl phenoxy)-2-propanol as a starting material. The halide, B. P. l18-124 C./4 mm, ofthis alcohol, which is formed by reaction with thionyl chloride, is reacted with ethanolamine to form the secondary amino alcohol 1-(o-sec.-butyl phenoxy)-2-propyl ethanolamine, M. P. 69.57l.5 C. The introduction of the N-benzyl group is accomplished as described in Example 1 in the presence of sodium bicarbonate. The resulting tertiary amino alcohol which distills at 162-172" C. at 0.35 mmhis converted to the halide by reaction with thionyl chloride to form N-(o-sec.-butylphenoxyisopropyl)-N-benzyl- 8-chlorethylamine hydrochloride, M. P. 142-l44 C.

Example 18 N-(p-hydroxyphenoxyisopropyl) -N-benzyl [3- chlorethylamine hydrochloride:

HO QO (report-p11;

To prepare this compound, N-(p-benzyloxyphenoxyisopropyl) -N-benzyl-,8 chlorethylamine hydrochloride (Example 19) is refluxed with 6 N alcoholic hydrochloric acid for 2 hours. This treatment removes the o-v'benzyl group and the p-hydroxy compound is recovered by concentrating the acid solution, M. P. 139-141" C.

:l-t'emre mam-mammalian;

e enemas,

r. sem cnmmm 1- (p-be'nzyloxyfihenoxy) Q 2 -"propan61is "prepared from hydroguinonemenobenzyl ether and propylene chlorohydriflinthe manner described -inzspreviousr exampies. "fil'zescmdezgprnductseparates iromiireaction 'mixtme ion tfiooling iand :"is redissolved by addition of more alcohol. The l- (p-benzyloxyphenoxy) =2gpropanol, M. P. 104- 105 C. is. purified .by recrystallization-from benzene.

A chloroform solution oi l-(p-benzyloxyphenoxy)-2-propanol is treated with thionyl chloride as described for Example 4. The chloro compound is recrystallized from alcohol .and mltszdtG'lSQtC.

Titty-"five ;1grams "of N 'jtpmenzyl'oxyphenoxyiisopropyl') =eth'anolam1ne is benzyla'td with 23 vgspfinenzyl ."cliioric'ie 'as"described iniExample '4.

"Dry :hjdrogen :bl'iioride Li's :p'assed into an 'ether solution or the ."crude prddut ltoitorm the lilyidroz'ililoride =salt wliich'rmelts "at :109Tfi--'I1"2 C. art-er *recrystallization "from racetone.

"Zflie i-N -;'gp- JbenzyioxyphenoXyi WropyI) "N- *benzylethanolammeiis'treated"with'ithiorlylfclilorridein"eiilordfornrsollition asdesefrbediinprevi- 'folIsexamplesftoffm the bachl'ore'thylammehy- "drochioride, "M.'iP.. "1"5215'4 N (p-benzylphenoxyisapmpyl) N benzyl-pchlorethylamine hydrochloride:

'N-CHi-CHz-CLHCI In this preparation the proeedureof Example 4 will be followed using as a starting material an equimoiar:Bamouxrt dfip=benzylphenorin place of p-"cre'sol. llhe sodium balt df tlie p benzylphenol which is prepared with sodium hydroxilie is refluxed together with :propylene chlorohydrin to obtain.p-benzylphenoxyisopropanol.

' "The end productis *form'eiifinthei'manner @described under Example 4 by halogenationof the p-benzylphenoxyisopropanol benzene solution l with thionyl chloride to 'form the halide of the compound which, in turn, .is reacted with ethanolamine to form the secondary amino "alcohol. The N- ben'zyl 'group is then introduced as described in Example 4 :byheating the secondary amino alcohol with benzyl chloride. Theresult- .ing .te'rtiar-y .amino walcohol is then reacted "with ithionylhloride .to produce N-ga benzylphenoxy- 'isopropyl) .-.Nb'enzyl -.p-.ch1orethylamine:hydrochloride.

ammpleezr 'N fiefbromophenoxyisopropyl) N 'bflzflipchlorethylamine hydrochloride:

In'this preparation the procedure of Example 4 will be followed using as a -starting material an "equimeiar amoriiit of obromophnol in place of 'esol. The sddiliin alt of the 'o -bromoph'enol whichis prepard w ith sodium hydroxi e is -refluxed together with propylene'chlorohydiin to obtain o-bromophenoxyisopropanol.

The end product is formed in the manner described-'un'der -Example 4 b halogenation 'orjthe 'o bromaphenoxyisopropanm with *thlonyl chloride to form the halide of the compound' whic'h, in turn, is reacted with ethanolamine'to form the secondary amino alcohol. The .N-benzyl group is then introduced as described in Example 4 by heating the secondary amino a'lcohol with benzyl chloride. The resultiri'g tertiary amino alcohol is then reacted with thionyl chloride to produce-N (o -bromophenoxyisopropanol) N- 30 benz'yl fi chlofiethylaminehydrochloride.

N t(phenoxyisopropanol) -.N- (p-chlorobenzyl .fl-chlorethylamine =-hydrochloride:

"feat-chi Example 23 in long "-In fthisipreparation th'e procedure '01- LEXa'nrple 41's 'fdllowefi' iisi'riglas a startingmaterialTanequimolar amount of resorciiiofmonomethyl ether in place of p-cresol. Ih'e2l-'-('rn-methoxyphenoXy) 2-propanol soformed distils at 1-07110-C.-./-1.mm. and is converted into'elam-methoxyphendxy) -:2- chloropropane by reaction with thionyl chloride as described under Example 4. Alkylation of ethanolamine by the ehloro compound .pr'o'duces N- (mmethoxyphenoxyisopropyl) ethanolamine which is benzylated with bnz'ylehloride in alcohol solution in the presence of sodium carbonate.

I chloride.

15 Finally, the tertiary amino alcohol is heated with thionyl chloride in chloroform solution to produce the fi-chlorethylamine hydrochloride.

Example 24 N-(3,4-dimethylphenoxyisopropyl) N-benzylfi-chlorethylamine hydrochloride:

This compound is prepared in the same manner as Example 4 with the substitution. in the first step, of 3,4-dimethylphenol for p-cresol. It melts at 143-145" '0.

Example 25 Nv (2-- isopropyl methylphenoxyisopropyl) N benzyl p chlorethylamine hydro,-

chloride:

CHa-CH-JJHB 1n the procedure of Example 4, thymol replaces p-cresol as a starting material. When the sodium salt of thymol is heated in alcohol solution with propylene chlorohydrin, 1-(2-isopropyl-5-methylphenoxy)-2-propanol is formed. This is halogenated by means of thionyl chloride to produce 1- (2-isopropyl-5-methylphenoxy) -2-chloropropane which is employed to alkylate ethanolamine. The secondary amine is benzylated and the hydroxy group is replaced by chlorine as described in Example 4 to yield the final product, M. P. l07-l09 C.

Example 26 N (o isopropylphenoxyisopropyl) N ben- V zyl-p-chlorethylamine hydrochloride:

CHs-CH-CHa With o-isopropylphenol as a starting material in place of p-cresol, the procedure of Example 4 is followed. In the first step an alcoholic solution of sodium salt of o-isopropylphenol is refluxed with propylene chlorohydrin to form the ether, l-(o-isopropylphenoxy) -2-propanol which is reacted with thionyl chloride. The resulting chloro compound when added to refluxing ethanolamine forms N-(o-isopropylphenoxyisopropyl) -ethanolamine which is benzylated with benzyl chloride. Finally, thionyl chloride in chloroform solution is employed to convert the tertiary amino alcohol to N-(o-isopropylphenoxyisopropyl)-N-benzyl-p-chlorethylamine hydro- M. P. 113.5115.5 C.

. Example 27 N- (p-sec.-butylphenoxyisopropyl) -N-benzyl-pchlorethylamine hydrochloride:

This compound is prepared in the same manner as Example 1, using 1-(p-sec.-butylphe- .noxy) -2-propanol in place of 1-phenoxy-2-propanol. Reaction of the; alcohol with thionyl chloride forms 1-(p-sec.-butylphenoxy) -2-chlo'- ropropane which is employed'to alkylate ethanolamine. Benzylation with benzyl chloride as described in .Example 1 yields the N-benzyl amino alcohol. The final step comprises reaction of the tertiary amino alcohol with thionyl chloride in chloroform solution. The p-chlorethylamine hydrochloride melts at 131-132 C.

Example 28 N (phenoxyisopropyl) N (2.4 dichlorobenzyl) -,5-chlorethylamine hydrochloride:

Cl CH1 solved in ml. of dry chloroform. Anhydrous hydrogen chloride is introduced until the solution is acid and then 8.4 g. of thionyl chloride is added. After the solution is refluxed for two hours, the solvent is evaporated at reduced pressure and the crude product is recrystallized from alcohol and ether. The purified N-(phenoxyisopropyl) N (2,4 dichlorobenzyl) p chlorethylamine hydroohloride melts at 116-1185 C.

Example 29 v N (o ethylphenoxyisopropyl) N benzyl-cchlorethylamine hydrochloride:

With o-ethylphenol as starting material, this compound is prepared by the process described in Example 4.

- Example 30 N-(o propylphenoxyisopropyl) N benzyl-fllchlorethylamine hydrochloride:

The preparation of this compound is efiected by following the directions under Example 4,

substituting equal molar proportions of o-propyl phenol for p-cresol.

Bymeplacingthe p-cresol at-Example :4 a stoichiometrically -eq'uivalent "amountoin -hut-ylphenol and following generally-the proeedur of Example 4;;there is obtained the above -e-ehlorethylamine {hydrochloride Example 32 N: (o.-isobutylphenoxyisopropyl) "11? ethane-3 .1173- chlorethylamine hydrochloride:

N-oHwon oLH-m The procedure of \Example 4 will be followed using an equivalent amount of.-o-isobutylphenol in place of p-cresol.

Example 33 N me eer h neer eqpreny ei-mandreor f lia em e edreeh e iw O CHa by chlorine with thiOlflyl'ch l'ol'id'e.

Example 34 N-(o benzylphenoxyisopropyl) N benzyl-,eohlorethylamine hydrochloride:

NcH2-cHho1.Hc1 CH2 With o-benzylphenol :as :the starting material the procedure of Example 4 will be followed to produce'the above compound, M.--.P. .l4.5-136.5 C.

'18 ifazamaile -35 A sodium ethogiidesolution was prepared by the addition of 629 'g. of sodiumato 250 ml. of absolute ethanol to which; was added, with stirring, 33.6 g. of p-iluorophenol. Propylene chlorohydrinwas added to theresulting clear) solution'zand the mixture .wasmefiuxednvernight. JiI'hezsodium chloride was removed :-.by filtration, -.;the alcohol by .rdistillation, and :the :resulting 1011 was dractionated-toyield 1 1-. (pefiuorophenoxy). -:2ezpropanol boiling at -1131?iC..at;;1f7..:mm. compound was converted etc a the vichloride :Lioy treatment of 25.8 gwojf thev a10Qh01FWithf23 .:g. ;of :thionyl phloride. ,Aiter .the .ens uing vigorous reaction .had ub ided the mixturewas -=shaken.=.and, allowedeto stand until 1 the evolution of ,ehydrogen .phloride hadceased. ese Leral dropsof zpyridinegwereadcled and the ;fia;sk,wfitted witlna,drying-,1tube,washedlowed .120 sfv md -f.0r1:1 hours. ,The imixturetzwa's then ;rei';l uxe,d 01 a gsteam ba-thhthei thionyl; ;ch10.- id removedmdervaauum@andctnemesultm nil ake llnin o-ethe .Mtertwashine theiethereal QL-Hti w th d lut h to h ri ta idiw-ftollqwed y dr fm lw i Dr erite,-.theietheruwastrremoyed by :d st .et 9 :th r sidu l-ei prfluo ophenoxy) -2-chloropropane was distilled off, 3.1;. llO-ll-l" C. ;.at 15 mm.

ist l e e hen lem newa heele lo :16hoursa n l, of I :the secondary.iamino alonhol;pre-

pared above, 10 .1 ,lg. ;of; :henzyl :chloride gland 5.9 o pot ssium. carbpnate was refiuxedlor 24 hourswith emcientstirrin :Solid material was removed, by; filtration of alcohol by :disti1la-.

tion andfihe crude residual oil wasldissolvedjn 20.0,:m1h of 110.9% hydrochloric: acid. Cooling nth-e arcidsoluti-on to 5 1C; :6 .9 ;;g. of: solid :so dium nitrite :was ,.-added slowly with vigorousstirring. After hour; the :cold solution :was-vextractediwithmtwo 1.0.0. mleportions oof ether,,made ]oasic with atr30 solution, of sodium hydroxide. and the, basic-solution :Was extractedzwithrthree 10.0 .ml.,. po'rtionsiof ether. After. drying these combined nether lextracts :mIerDrierite (the ether ewas removted distillationandtheresulting oil iractiona'ted lt'o yield N henzvl i N -v,[5-'( p-fluorophenoxyilisopropylfl ethanolamine, .boi1in'gfat18.0 181. -C. at QAunm. M912 g.,..of; thertertiary amine. prepared aboveswas addeda r'glradue'dlly10o125ml. of :redistilled thionyl chloride. After the initial wigorousreaction "had subsided thea'mixture .zwas qrefluxed zfor 1 izh'our and the v.zexcess lthionyllzchloride mas nremoved under reduced ."pressure. ris'everalrarecrystalliza ations not. the lresiduezifrom absolute ;ethanol. and

19 other provided N-(p-fiuorophenoxy-isopropyl)- N-benzyl-fi-chlorethylamine hydrochloride, melting at l36-l37 C, V V

' Example 36 N (o-fiuorophenoxyisopropyl) -N benzyl chloroethylamine hydrochloride:

N-CH -CH -CLHCl This compound was prepared using a procedure identical with that described above with the exception that o-fiuorophenol was utilized as a starting material in place of p-fi-uorophenol. The o-fluoro isomer so prepared had a melting point of l58-159 C. after recrystallization.

.In the foregoing examples hydrochlorides and hydrobromides according to this invention are exemplified. However, it will be understood and readily appreciated by those skilled in the art that the foregoing examples will illustrate the structure of organic or inorganic salts generally and will serve as specific examples of those organic and inorganic salts heretofore mentioned specifically by the writing in the several foregoing illustrative structures of the chemical symbols for the several acid groups heretofore specifically mentioned or of the acid group of any other desired organic or inorganic acid for the I-ICl or HBr in the several foregoing examples, respectively.

It will similarly be self-evident to those skilled in the art that in the foregoing examples illustrative of the production of chloride hydrochlorides by the procedures described, bromide hydro-- bromides will be produced with the use, for example, of thionyl bromide in place of thionyl chloride in the final step. Thus, the foregoing specific examples of chloride hydrochlorides serve a specific examples of bromide hydrobromides by simply replacing Cl.HCl in the several formulae with Br.HBr.

The foregoing examples illustrate the salts contemplated by this invention. The bases contemplated by this invention according to the broad and more particular structural formulae herein disclosed are specifically exemplified as will be obvious to anyone skilled in the art by reference to the foregoing specific examples with the removal from the structures illustrated thereby of the acid group, i. e., HCl or HBr.

As will be apparent, the organic and inorganic salts contemplated by this invention will be prepared from the bases in a manner usual and well known to those skilled in the art, as by neutralizing the bases with organic or inorganic acids.

The bases contemplated by this invention will be formed by carefully interacting the salts contemplated by this invention and herein exhaustively exemplified with one molecular equivalent of a strong alkali such, for example, .as sodium hydroxide, potassium hydroxide, lithium hydroxlde, or the like, in aqueous solution say, for

example, a 1-10% solution at room temperature or below and the bases so liberated are isolated with the aid of a water-immiscible solvent such as ether or benzene. The preparation of free bases 20 optically inactive and optically active forms of the compounds contemplated by this invention are all included within the scope of this invention.

The various types of compounds having the structure embodying this invention as illustrated by the above specific examples and examples of the various types of compounds will be readily prepared by the general methods of preparation described above as exemplified by the description of the preparation of the several specific examples. The starting material for the preparation of any given compound Within the structure contemplated by this invention will be found among known compounds, or, its structure being obvious with reference to any particular compound desired to be prepared, will be readily prepared by known methods.

This is a continuation-in-part of our application Serial Number 97,926, filed June 8, 1949, now abandoned.

What is claimed is:

l. A compound of the class consisting of a free base and its acid addition salts, the free base having the formula:

spent-0112 01 i 3. The compound having the structure:

N-CH2-CHi-Cl.HCl C OH2 4. The compound having the structure:

5. The compound having the structure:

22 6. The compound having the structure: REFERENCES CITED The following references are of record in the file of this patent:

C 5 UNITED STATES PATENTS Number Name Date JAMES F. KERWIN 2,495,772 Rieverschl et a1. Jan. 31, 1950 GLENN E. ULLYOT. 

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACID ADDITION SALTS, THE FREE BASE HAVING THE FORMULA: 